JAK-STAT pathway inhibition modulates centrally sensitised default mode network hubs in rheumatoid arthritis pain
Kristian Stefanov, Joel T. Parkinson, Flavia Sunzini, Salim Al-Wasity, Chelsea M Kaplan, Andrew Schrepf, Eric Ichesco, David A. Porter, Graeme A. Keith, Andrew McGucken, James Brock, Norah Aldehmi, Luz Paramo-Fiscal, Aysin Tulunay-Virlan, Maxine Arnott, Tyrone Lau, Carl Goodyear, Gregor Thut, Nicholas Shenker, Iain B. McInnes, Daniel J. Clauw, Jonathan Cavangh, Neil Basu
medRxiv July 14, 2026 preprint DOI: 10.64898/2026.07.12.26356929 (opens in new tab)
Study at a glance
AI-extracted from the abstract| Characteristics | Observational cohort and interventional study |
|---|---|
| Population | Rheumatoid arthritis patients |
| Interventions | JAK-STAT pathway inhibitors anti-TNF therapy transcranial magnetic stimulation |
| Topics | Default mode network |
| Keywords | Transcranial magnetic stimulation Rheumatoid arthritis Peripheral Inflammation Immune system Chronic pain Posterior cingulate Central nervous system Biomarker Inferior parietal lobule |
| Key findings | Blocking peripheral JAK-STAT signalling reduces both objective and subjective nociplastic pain in rheumatoid arthritis, revealing a localized inflammatory driver behind a traditionally non-inflammatory pain state. |
Abstract
Abstract Nociplastic pain represents a major burden across immune-mediated inflammatory diseases (IMIDs). It is hypothesised, but not yet demonstrated, that peripheral inflammation promotes nociplastic pain by bottom-up sensitisation of the central nervous system (CNS). In rheumatoid arthritis (RA), a prototypic IMID, we used ultra–high field (7T) brain resting-state functional MRI to evaluate whether peripherally targeted anti-inflammatory therapies alter a biomarker of bottom-up CNS sensitisation: inferior parietal lobule (IPL)–insula connectivity. In discovery and replication cohorts, JAK-STAT pathway inhibitors significantly shifted IPL–insula connectivity toward a normalised pattern. This effect was not seen with placebo or anti-TNF therapy. Moreover, after performing an agnostic whole-brain multivariate analysis of functional connectivity change related to JAK-STAT inhibition, the posterior cingulate cortex (PCC) was identified; like the IPL, a major hub of the default mode network (DMN). We then probed the DMN with transcranial magnetic stimulation in an independent RA cohort. Active, but not sham, stimulation altered DMN connectivity and reduced peripheral blood monocyte pSTAT3 function, a surrogate of immune inactivation, suggesting a bi-directional brain–immune circuit. Together, these findings provide the first human experimental evidence that peripheral JAK-STAT pathways contribute to nociplastic pain in IMIDs. One Sentence Summary Blocking peripheral JAK-STAT signalling reduces both objective and subjective nociplastic pain in rheumatoid arthritis, revealing a localised inflammatory driver behind a traditionally non-inflammatory pain state.
Comparable studies
Other observational and cohort studies on default mode network, most cited first.
| Study | Year | Design | Participants |
|---|---|---|---|
| A default mode of brain function Normal adult human brain | 2001 | Observational study | |
| Resting-State Functional Connectivity Reflects Structural Connectivity in the Default Mode Network Healthy subjects | 2008 | Observational cohort | |
| Meditation experience is associated with increased cortical thickness Participants with extensive Insight meditation experience and matched controls | 2005 | Observational cohort | n = 20 |
| Meditation experience is associated with differences in default mode network activity and connectivity Experienced meditators and matched meditation-naive controls | 2011 | Observational cohort | |
| The precuneus/posterior cingulate cortex plays a pivotal role in the default mode network: Evidence from a partial correlation network analysis Healthy subjects | 2008 | Observational study |